2. The National Institute for Health Research is charged with
developing and supporting a health research system in
which the NHS supports leading edge research focused on
the needs of patients and the public.
Funding is allocated through the BRCs and CBRCs through
competitive tender.
In August 2011, the NIHR invested a further £800 million in
health research over 5 years.
CHERUB is part of this investment.
CHERUB – uniquely - combines the research efforts of the
five ‘comprehensive’ BRCs
The Comprehensive Biomedical
Research Centres (CBRCs)
3. CHERUB Steering Committee
Name Institution Role
John Frater University of Oxford Scientific lead
Sarah Fidler Imperial College London Clinical lead
Jonathan Weber Imperial College Chair of TSC
James Williams, Lucy Dorrel University of Oxford Laboratory
Steve Kaye Imperial College Laboratory
Simon Collins i-Base People living with HIV
Representation
Deenan Pillay, Ravi Gupta University College London Laboratory
Paul Kellam Sanger Institute / UCL Deep sequencing
Mike Malim,, John Cason,
Julie Fox
Kings College London Laboratory & Biobank,
clinical centre
Andrew Lever, Mark Wills University of Cambridge Viral replication assay
Jane Anderson, Adrian Palfreman BHIVA chair
Mark Nelson, Mark Bower, Martin Fisher,
Sabine Kinloch, Nneke Nwokolo, Caroline
Foster, Iain Williams
C&W Hospital,
Brighton, Royal Free,
Dean street, St Marys Hospital, Mortimer Market
UK Clinical leads
4. Development of ‘stock’ assays
Proviral DNA qPCR (integrated, total, episomal)
Ultra-low viral load assay (Steve Kaye IC)
Quantitative replication competence (Andrew Lever
Cambridge)
Sequencing platforms
Immunology platforms
New platforms
Scientific work led by Dr John Frater
Determining Endpoints: Assay Development
5. 001 : IVIG in PHI
003: Chemotherapy protocol
Viral reservoir characterization SPARTAC study
Observational studies CHERUB-yc, HEATHER
Future planned studies awaiting funding decision:
005: HDACi + Vaccine in PHI
HDACi + ART + chemotherapy
HDCAi + Vaccine in ART-treated acute infection
Generation of autologous HIV ‘vaccine’
Clinical Cohorts in Development
6. CHERUB 001: IVIG in Primary HIV Infection
Julie Fox (King’s College London)
Reduction of the HIV-1 reservoir in resting CD4+ T-
lymphocytes by high dosage intravenous
immunoglobulin treatment in ART treated acute
infection : a proof-of-concept study
CHERUB 001
Rebound of residual plasma viremia after initial decrease following addition of intravenous immunoglobulin to effective antiretroviral
treatment of HIV.
Mellberg T, Gonzalez VD, Lindkvist A, Edén A, Sönnerborg A, Sandberg JK, Svennerholm B, Gisslén M
AIDS Res Ther. 2011 Jun 28;8:21
7. Primary outcome: quantification of HIV DNA week 48
Secondary outcome: immune activation Gut biopsy sub study
Study profile
N = 10
Recent HIV infection within 12 weeks of infection
Immediate ART Truvada, Darunavir, Ritonavir, Raltegrvir
2x HIV VL<50 four weeks apart
Randomisation
ART + 30g IVIG
0.4g/kg/day5 days Continue ART
8. Proof of principle study N=25
AIM
To investigate the impact of cytotoxic chemotherapy agents in addition to ART on
surrogate markers of viral reservoirs.
Primary Endpoints
Comparison of proviral DNA quantification between baseline and at 12 weeks post-
chemotherapy
Cytotoxic agents used in HIV+ve individuals with malignancy include:
Kaposi’s sarcoma – Liposomal doxorubicin (Caelyx) or liposomal daunorubicin
(Daunoxome) or Paclitaxel
Non-Hodgkin’s Lymphoma – ‘RCHOP’: Rituximab, Cyclophosphamide, Doxorubicin,
Vincristine, Prednisolone
Hodgkin’s Disease – ‘ABVD’: Doxorubicin, Bleomycin, Vinblastine, Dacarbazine
CHERUB 003 – ‘Chemotherapy’
Prof Mark Bower
10. Definition of PHI
laboratory evidence of infection within 6 months of a
previous negative test, <3 bands WB, RITA incident, antibody
negative PCR+
Randomisation to one of three arms:
48-week short course ART (ART-48)
12-week short course ART (ART-12)
No therapy (Standard of Care SOC)
Primary end point
time to CD4 <350 cells/mm3 or long-term ART initiation
SPARTAC: Trial Design
N Engl J Med. 2013 17;368(3):207-17
12. N= 40 participants randomly selected from ART48 vs SOC
Quantification of total integrated HIV DNA at baseline and
week 52
Results: HIV-1 reservoir after 48 weeks of treatment
strongly predicted disease progression, with total HIV-1
levels being more predictive than integrated levels.
Dr John Frater: will present at KL July 2013, Towards a cure
meeting and IAS oral late breaker
Characterisation of measures of viral
reservoirs in SPARTAC
13. HEATHER
Individuals with defined HIV acute infection (< 12 weeks from
previous negative test) initiating immediate ART suppressed on
treatment for > 2 years
CHERUB-yc
Perinatally HIV infected young people age > 10 years: either
started on ART within first year of life and still suppressed vs ART
started >1 years of age
Primary outcome
total and integrated HIV DNA
Observational studies
14. REACH
Generation of autologous vaccine for future ex vivo
studies from treated acute infection (Eric Arts-Amfar
application under review)
ART treated from acute infections Vaccination plus
HDACi with more potent agent Romedipsin :
dependent on outcome of single dose ACTG Mellors
study
Future studies planned
15. Proof of principle pilot study n = 50
Industry (Merck, Okairos ) academic partnership
funding sought from MRC DCS
Recent HIV infection (< 12 weeks).
Patients with recent HIV infection
Start immediate ART
ART + Vaccination + HDACi- Vorinostat
Primary Outcome: Quantification of HIV reservoir.
CHERUB 005
REACH: Recent HIV infection: Eradication by Activation of the
HIV reservoir: A proof of concept trial
17. Primary Study end point
Comparison between arms Log10 integrated proviral HIV DNA /CD4 cell at week 38 & 40
REACH Regimen
Week 0 2 4 8 12 23 24 28 32 33 34 38 40
Day in week 1 1 1 1 1 1 1 1 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 1 1
(V)accine V V
Vorinostat 1 2 3 4 5 6 7 8 9 10
18. All interesting UK health care professionals providing
care for PLWHA may see patients who ask questions
about UK HIV “cure” research
May refer potentially interested patients into ongoing
studies
May be interested in working with the collaboration
in laboratory based research or developing new
clinical trial ideas
Why might you be interested?
http://www.cherub.uk.net/@ukcherub
Hinweis der Redaktion
Spartac was an open RCT 1:1:1 randomisation across 8 different countries The planned sample size of 360 participants was estimated using CASCADE data,19,20 providing 90% power with significance level 5% to detect a relative reduction in the risk of progression to the original primary endpoint (CD4 <350 cells/mm3) of 50% and 25% in ART-48 and ART-12, respectively, versus SOC, assuming recruitment over 18 months with minimum 3.5 years follow-up and 10% lost to follow-up.
This graph compares the actual time difference in weeks to reach primary endpoint between the armsART48 delayed time to primary endpoint by 65 weeks compared with SOC. This was however, not significantly longer than time spent on therapy
